tbuckley/cabot-search huggingface dataset:
PATH-26. COMPLEMENTARY CLASSIFICATION APPROACH TO RESOLVE LOW-SCORE RESULTS FROM THE DKFZ METHYLATION CLASSIFIER FOR CNS TUMOR DIAGNOSTICS
Authors: Omkar Singh, Drew Pratt, Zied Abdullaev, Martha Quezado, Kenneth Aldape, Patrick Cimino
Journal: Neuro-Oncology (2022)

Abstract DNA methylation-classification using the DKFZ CNS tumor classifier is highly useful, but experience indicates that approximately one-third of clinical cases do not reach the confidence threshold (0.84) for a definitive match. A low-confidence score can be observed for a variety of reasons, and addressing such instances is not always clear. We developed a complementary classification approach that differs from the DKFZ classifier in several important ways. First, it utilizes a new reference set of several thousand samples, utilizing the entire ~850k probe set on the EPIC array. Second an alternative classification approach, it establishes multiple (50) classifiers by dividing the probes into 50 independent bins, allowing dual measurements of both an overall confidence score, as well as a consistency score. To evaluate this approach, we first evaluated a set of well-classified samples (N=521, DKFZ family score &amp;gt; 0.84) as ground-truth, showing that our bin-based approach was equivalent (100% accuracy) in well-classified samples. Second, we then evaluated a set (n=329) of samples that did not match to the 0.84 threshold on the DKFZ classifier. Using cutoff of 0.8 consistency score and 0.7 confidence score, we identified 99/329 cases with a match. To evaluate the potential ground-truth of our findings, orthogonal data was used to validate matches in our classifier. For example, many of our matches to GBM showed the expected abnormalities (combined +7/-10 CNV and TERT promoter mutation). Two cases that received low-score IDH-glioma matches by DKFZ matched to K27-altered-DMG in our classifier and were later shown to harbor the H3-K27M mutation. One case that received a low-score suggestion of GBM-MES on DKFZ matched in our classifier to PXA; this was then shown to harbor the expected BRAFV600E mutation. Overall, our method may add to and complement the DKFZ classifier as a means to resolve a subset of otherwise difficult-to-classify CNS tumors.
DNAR-01. CHROMOTHRIPSIS, ONE MAJOR GENETIC INSTABILITY FACTOR IN GLIOBLASTOMA, IS RARE IN IDH-MUTANT GLIOMAS
Authors: Baptiste Sourty, ëtitia La Basset, Emmanuel Garcion, Audrey Rousseau
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas, and IDH-wildtype glioblastomas (GBM). GBM display genomic instability, which is favored by two genetic events leading to massive chromosomal alterations: chromothripsis (CT) and whole-genome duplication (WGD). Those events are scarcely described in IDH-mutant gliomas. The better prognosis of IDH-mutant gliomas may be in part related to their greater genomic stability compared to GBM. METHODS Pangenomic profiles of 301 adult diffuse gliomas were analyzed at initial diagnosis by SNP arrays, including 196 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 oligodendrogliomas). We further analyzed 16 IDH-mutant recurrent gliomas (11 astrocytomas and 5 oligodendrogliomas). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening. Survival data were compared using Kaplan-Meier method and categorical variables using Chi2 test. RESULTS At initial diagnosis, 37 GBM (18.8%) displayed CT (mainly affecting chromosomes 12, 9 and 7) versus five IDH-mutant gliomas (4.8%) (p = 0.0007). The latter were all high-grade astrocytomas. No oligodendroglioma or grade 2 astrocytoma displayed CT. There was a trend towards higher occurrence of CT in GBM versus high-grade IDH-mutant astrocytomas (p = 0.0589). WGD was detected at initial diagnosis in 18 GBM (9.2%) and 9 IDH-mutant gliomas (of any subtype and grade; 8.6%). Over 75% of chromosomal losses occurred after WGD. Neither CT nor WGD was associated with overall survival in GBM. At recurrence, one grade 4 IDH-mutant astrocytoma displayed CT and another one, WGD with CT. CONCLUSION CT is rare in IDH-mutant gliomas compared to GBM. The absence of CT in oligodendrogliomas and grade 2 astrocytomas may contribute to their greater genomic stability and better prognosis. CT occurrence in high-grade IDH-mutant astrocytomas may underlie aggressive biological behavior. WGD is a rare early event occurring equally in IDH-mutant gliomas and GBM.
NCOG-27. A SINGLE-INSTITUTION RETROSPECTIVE SERIES OF SARS-COV-2 INFECTION IN ADULT GLIOMA PATIENTS
Authors: Tyler Lanman, Amber Ruiz, Seema Nagpal
Journal: Neuro-Oncology (2022)

Abstract A subset of cancer patients is particularly vulnerable to SARS-Cov-2 infection; however, real-world outcomes-based data on primary central nervous system tumor patients is sparse. This retrospective case series describes a cohort of adult glioma patients seen at Stanford Cancer Center between 1/20/2020 through 5/24/2022 who contracted SARS-Cov-2. We identified 18 patients with a diagnosis of glioma, with a median age of 54 years, who were infected with Covid-19. One patient contracted Covid-19 twice during this two-year period. Of these patients, four had pathology confirmed low-grade glioma, defined as oligodendroglioma or astrocytoma WHO grade 2, and 14 patients had high-grade glioma, defined as astrocytoma or glioblastoma WHO grade 4. Median KPS at time of infection was 70. Six individuals had notable cardiovascular comorbidities including coronary artery disease, obesity, and/or diabetes. All but one patient was vaccinated against Covid-19, and 6 were taking dexamethasone at the time of infection. Three patients required hospital admission for management of Covid-19 symptoms, although none required ICU-level of care. None died from Covid-related complications; however, two died from complications of their underlying cancer at the end of study. Our data suggest that glioma patients seen at Stanford Cancer Center do not experience an exceptionally high Covid-19 infectivity, hospitalization, or mortality rate, especially when compared to other vulnerable populations such as lung cancer patients. High vaccination rates, fairly low prevalence of cardiovascular comorbidities, and adherence to pandemic precautions among this cohort may have contributed to these results.
NIMG-28. USE OF NEUROIMAGING TECHNIQUES IN GLIOMA PATIENTS – RESULTS OF AN INTERNATIONAL SURVEY ON BEHALF OF THE EORTC BRAIN TUMOR GROUP
Authors: Philipp Lohmann, Marion Smits, Evangelia Razis, Martin Kocher, Karl-Josef Langen, Filip de Vos, Martin Bendzsus, Enrico Franceschi, Anca-Ligia Grosu, Inge Compter, Damien Galanaud, Jaime Gallego Pérez de Larraya, Jens Gempt, Peter Hau, Nicolaus Andratschke, Joerg-Christian Tonn, Gelareh Zadeh, Michael Weller, Matthias Preusser, Norbert Galldiks
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Multimodal imaging offers the potential to provide valuable diagnostic information in brain tumor patients. Considering the increasing number and availability of advanced neuroimaging techniques, selecting, and applying the best modality may be therefore difficult. The present survey was carried out to evaluate the preferred use of various neuroimaging applications in patients with glioma. METHODS An online survey with 31 questions was distributed to 262 centers associated with the EORTC located in 34 countries. Subsequently, this survey was promoted by EANO and SNO via social media and newsletters. RESULTS A total of 77 responses, predominantly from radiation oncologists (36%) and neurooncologists (31%), were evaluated. Most responses came from university hospitals and research institutions (68%), mainly from Europe (89%). Almost half of these centers (48%) examined more than 100 glioma patients per year. All institutions had access to MRI, 94% to CT, 67% to PET or PET/CT, and 27% to hybrid PET/MRI. A total of 56% of institutions used RANO criteria for the evaluation of imaging findings. In addition to structural MRI, most institutions routinely performed advanced MRI, followed by CT, PET, and hybrid PET/CT (74%, 42%, 32%, and 23%, respectively). Regarding PET, 64% of centers used the amino acid tracer O-(2-[18F]fluoroethyl)-L-tyrosine, followed by 2-[18F]-fluoro-2-deoxy-D-glucose (45%). Twenty-five percent of centers performed intraoperative MRI, and 10% intraoperative CT. In addition to structural MRI, the preferred additional imaging methods were perfusion-weighted MRI, diffusion-weighted MRI, amino acid PET, and proton MR spectroscopy (83%, 75%, 60% and 56%, respectively). CONCLUSION The results of this international survey provide insights into the use of neuroimaging techniques in neuro-oncology centers. The availability, use, and assessment of neuroimaging in glioma patients varies from country to country. Our results highlight the importance of global activities towards further standardization of neuroimaging in brain tumor patients, such as the RANO working groups.
EPCO-11. GATEKEEPER INACTIVATION DRIVES TUMOR PROGRESSION TO GRADE IV ASTROCYTOMA
Authors: Anja Hartewig, Kirsi Granberg, Serafiina Jaatinen, Aliisa Tiihonen, Matti Annala, Elisa Vuorinen, Anni Kivinen, Minna Rauhala, Kendra Maass, Kristian Pajtler, Olli Yli-Harja, Pauli Helén, Joonas Haapasalo, Wei Zhang, Hannu Haapasalo, Matti Nykter
Journal: Neuro-Oncology (2022)

Abstract IDH-mutant low-grade diffuse astrocytomas frequently progress to grade IV astrocytomas with implications for patient prognosis. To better understand this process, we applied whole-genome and transcriptome sequencing to matched tumor samples collected before and after progression to grade IV astrocytomas from five patients. All tumors carried an IDH1 mutation. The number of chromosomal rearrangements was increased between 1.3 and 3.5-fold in the tumors upon progression, with the exception of one case, in which the increase was only 1.03-fold. This case exhibited a hypermutation signature caused by homozygous deletion of the MSH2 gene, which encodes a member of the DNA mismatch repair complex. The most common genomic alterations acquired at progression were homozygous deletions in the CDKN2A/ RB1 -pathway or hemizygous deletion of PTEN. Additionally, PDGFRA was amplified in two grade IV tumors, with concordantly increased expression. For one of these cases, a PDGFRA-amplified subclone is likely to be present already in the low-grade astrocytoma. We further detected intrachromosomal rearrangements closeby the genes NRG3 in the progressed tumors as well as in the The Cancer Genome Atlas (TCGA) cohort. The expression of NRG3 decreased with increasing grade in the TCGA cohort and the gene was frequently deleted. Lower NRG3 expression was associated with shorter survival in the TCGA cohort. Several miRNAs showed differential expression upon progression. For two miRNAs the predicted targets were associated with cell cycle regulation and we detected inverse correlation between miRNA and target mRNA expression. While progression seems to occur via different pathways, the predicted outcome for many of the alterations was the inactivation of tumor suppressor genes and further dysregulation of cell proliferation.
BIOM-51. ELUCIDATION OF THE TRANSCRIPTOMIC CONSEQUENCES OF KLF4 AND TRAF7 MUTATIONS IN SECRETORY MENINGIOMAS
Authors: Signe Regner Michaelsen, Paul Cloos, Helle Broholm, Jens Johansen, Ulvi Ahmadov, Tiit Mathiesen, Lasse Kristensen, Bjarne Winther Kristensen, Klaus Hansen
Journal: Neuro-Oncology (2022)

Abstract Secretory meningioma (SM) is a benign histological meningioma subtype frequently located in the central skull-base, complicating surgical removal, highlighting the need of gentle targeting treatment alternatives. SM tumors arise from the arachnoid layer in the meninges and are associated with a hotspot p.K409Q mutation in KLF4 combined with different mutations in TRAF7. The objective of this study was to identify how KLF4 and TRAF7 mutations alter signaling in SM tumors.The study includes 16 FFPE samples from SM tumors and three arachnoid cysts as normal-tissue reference. All tissues were histologically confirmed, followed by genomic sequencing of KLF4, TRAF7, NF2 and TERT-promoter (C220T/C228T) using a customized NGS panel. Gene expression profiles were analyzed using NanoString Pan-cancer Progression and Pan-cancer Pathways panels, which resulted in measurement of 1,202 unique transcripts over background level.All 16 SM tumors presented the KLF4p.K409Q mutation, of which 12 had mutation in TRAF7 (four being p.N520S), while no cysts had mutations in these genes. Neither tumors nor cysts had NF2 or TERT-promoter mutations. PCA analysis showed different RNA expression profiles for SM tumors and cysts, while TRAF7 mutation was without influence on the overall gene expression patterns in the tumors. Sub-analysis found increased KLF4 expression in TRAF7-mutated SM tumors versus non-mutated tumors and cysts at the RNA level, while TRAF7 expression was stable in all samples. In total 98 genes were found differentially expressed (54 up- and 44 downregulated) with a log2-fold change over 1 and an adjusted p-value under 0.05 in tumors versus cysts. Further analyses are planned to explore and validate these results. In conclusion, we find that the KLF4p.K409Q mutation correlates more strongly with SM histology, than the TRAF7 mutation, and that SM tumors have gene expressions profiles that are distinct from normal arachnoid tissue for a number of disease relevant genes.
CTNI-49. EARLY SIGNAL OF ACTIVITY FROM A PHASE 2 STUDY OF ST101, A FIRST-IN-CLASS PEPTIDE ANTAGONIST OF CCAAT/ENHANCER-BINDING PROTEIN Β (C/EBPΒ), IN RECURRENT GLIOBLASTOMA (GBM)
Authors: Fabio Iwamoto, Vinai Gondi, Nicholas Butowski, Gerald Falchook, Anja Williams, Katherine B Peters, Jeff Evans, Nehal Lakhani, Meredith McKean, Stefan Symeonides, Benjamin Ellingson, Jim Rotolo, Gina Capiaux, Erol Wiegert, Rob Michel, Steve Kaesshaefer, Alice Bexon
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND C/EBPβ is a transcription factor that is active during embryofetal development but held in an inactive state in most mature cells (Zahnow 2009). C/EBPβ activates a proliferation/survival gene signature in multiple cancers, where it inversely correlates with disease prognosis and survival. ST101 is a cell-penetrating peptide antagonist of C/EBPβ. ST101 exposure leads to selective tumor cell death in multiple human cancer cell lines, including GBM, without impacting normal cell viability. In vivo, ST101 displays rapid uptake into multiple organs, the ability to cross the blood-brain barrier, and a long plasma half-life due to its resistance to degradation. It has potent anti-tumor activity in multiple GBM models, as a single agent or in combination, which supported moving into clinical development. TRIAL DESIGN: This phase 2 study is enrolling adult patients with GBM that has recurred or progressed after one standard treatment regimen (surgery, radiotherapy +/-temozolomide). Patients require measurable disease at baseline and at least 3 months from prior radiotherapy. Subjects receive the recommended phase 2 dose of ST101 (500mg IV weekly). Recruitment in the phase 2 portion of this trial began in January, 2022. RESULTS As of June 1, 2022, 14 GBM patients were enrolled. One patient has a confirmed mRANO partial response (PR) after 18 weeks of therapy, seven patients have not reached the first on-study assessment and six patients progressed. The median duration of therapy was 5 weeks. ST101 has a favorable safety profile with minor infusion related reactions being the most common adverse event. Based on the confirmed PR, the GBM cohort will be expanded. CONCLUSION This first-in-class C/EBPβ inhibitor, ST101, showed an early signal of activity in recurrent GBM. More extensive follow-up and clinical experience will be presented as this trial expands and matures.
RADT-06. SPARING OF MOTOR STRUCTURES IN ADJUVANT RADIATION THERAPY AFTER RESECTION OF BRAIN METASTASES: APPLICATION OF NTMS-DERIVED DTI-BASED MOTOR FIBER TRACKING IN ADJUVANT STEREOTACTIC RT TREATMENT PLANNING
Authors: Christian Diehl, Enrike Rosenkranz, Martin Mißlbeck, Maximilian Schwendner, Nico Sollmann, Kerstin Eitz, Denise Bernhardt, Sebastian Ille, Bernhard Meyer, Stephanie Combs, Sandro Krieg
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Resection of brain metastases (BM) close to the motor cortex and the corticospinal tract (CST) bears a significant risk for treatment-related morbidity. Navigated transcranial mapping (nTMS) combined with diffusion-tensor-imaging (DTI) based fiber tracking (DTI-FTTMS) is a valuable tool to guide the neurosurgeon along the CST to preserve motor function. This study aims to proof the practicability of DTI-FTTMS in local adjuvant stereotactic RT planning in the management of BM. Method: Pre-surgical generated DTI-FTTMS-based CST reconstructions of 24 patients with 25 resected BM were incorporated into the RT planning system and elastic fused with planning imaging. The CST was delineated as the planning risk volume (PRV-FTTMS). Fractionated stereotactic intensity-modulated RT (IMRT) plans (7 x 5 Gy) were retrospectively calculated and then optimized to preserve PRV-FTTMS. Areas covered by the planning target volume (PTV) were not spared (overlap). RESULTS In regular plans mean dose (Dmean) of complete PRV-FTTMS was 5.4 ± 2.5 Gy. Regarding PRV-FTTMS portions within the 8.75 Gy (25% of prescription dose) isodose level Dmean was 18.2 ± 4.3 Gy and after plan optimization 13.1 ± 3.8Gy (-28.0%, p &amp;lt; 0.001). Within the 17.5 Gy (50%) isodose line PRV-FTTMS Dmean was reduced by 31.7% from 24.3 ± 3 Gy to 16.6 ± 4.8 Gy (p&amp;lt; 0.001). There was no decline of the effective treatment dose, PTV Dmean in regular plans was 36.9 ± 0.7 Gy vs. 37.7 ± 1.4Gy (p=0.013) after adaption. PTV coverage (V35Gy(%)*100) did not change with plan optimization: 0.99 vs. 0.99 (p=0.43). Dose constraints of organs at risk were all met both in regular and optimized plans. CONCLUSION DTI-FTTMS based motor tracts could be implemented in the adjuvant stereotactic RT planning of cavities after resection of BM. A significant dose reduction of motor structures within critical dose levels seems possible without reducing PTV treatment dose. However, the functional benefit needs to be investigated prospectively within clinical trials.
RADT-18. PARTICLE BEAM RADIATION THERAPY PLUS TUMOR TREATING FIELDS IN THE TREATMENT OF NEWLY DIAGNOSED WHO GRADE 4 GLIOMAS: AN EARLY RESULT OF PHASE 2 SINGLE-ARM TRIAL
Authors: Xianxin Qiu, Jing Gao, Jing Yang, Jiyi Hu, Weixu Hu, Qingting Huang, Haojiong Zhang, Lin Kong, Jiade Lu
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVES Tumor Treating Fields (TTFields) is increasingly provided to patients with WHO grade 4 gliomas following radiotherapy. Particle beam radiotherapy (PBRT) represents a novel promising radiation approach with improved therapeutic ratio. This study was aimed to report an early result of TTFields in combination with PBRT for treating WHO grade 4 gliomas based on a prospective phase 2 trial from Shanghai Proton and Heavy Ion Center. METHODS This phase 2 trial was designed as a single-arm study to test the outcome of PBRT plus TTFields. Six patients with newly diagnosed WHO grade 4 gliomas receiving surgery, PBRT, temozolomide, and TTFields, from August 2021 to May 2022, were enrolled and analyzed. Tumor histologies based on the WHO CNS5 classification system were IDH-wild glioblastoma (n=4), IDH-mutant astrocytoma (n=1), and H3G34-mutant diffuse hemispheric glioma (n=1). For PBRT, all patients were irradiated with a baseline standard dose of 60GyE/30 utilizing proton. Carbon-ion boost of 15GyE/3 for tumor residual was performed for one patient prior to proton radiation. TTFields treatment was recommended to start soon after PBRT. RESULTS With a median follow-up of 5.5 months, all patients were alive at the time of this analysis; one patient with left thalamic glioblastoma had tumor progression of distant failure outside the radiation field at 4 months after partial tumor resection. The median interval between PBRT and TTFields was 2 days (range 1-22 days). No patient had dermatitis during PBRT. No severe TTField-related skin toxicity (Grade 3 or above) was observed. Five patients (83.3%, 5/6) developed mild skin toxicities (Grade 1) during TTField treatments. CONCLUSIONS Starting TTField early following PBRT is feasible for treating WHO grade 4 gliomas, the overall side effects are mild. Prospective studies with further follow-up are warranted to identify the outcomes of PBRT in combination with TTField in terms of survival and side effects.
BIOS-03. REAL WORLD CLINICAL OUTCOMES OF PATIENTS WITH DIFFUSE MIDLINE GLIOMA IN A LONGITUDINAL OUTCOMES REGISTRY
Authors: Timothy Stuhlmiller, Asher Wasserman, Jameson Quinn, Mark Shapiro, Santosh Kesari
Journal: Neuro-Oncology (2022)

Abstract We utilized the longitudinal clinical outcomes registry XCELSIOR (NCT03793088) to understand real world outcomes and treatment patterns among patients with diffuse midline glioma. A total of 74 patients were identified with a diagnosis of diffuse midline glioma by pathology or imaging (36 pediatric and 38 adult patients). Median age at diagnosis was 20 years. As of 6/1/2022, 45 patients had expired. Median overall survival (mOS) of the entire cohort was 16.2 months. Cox proportional hazard ratio analysis identified age as the only significant covariate for OS (pediatric HR = 1.59, p=0.04). Pediatric patients had a mOS of 12.9 months and adult patients a mOS of 18.9 months from diagnosis. Frequency of primary tumor location in this dataset was brainstem (35%), thalamus (23%), and pons (20%). Pons location was associated with worst survival (mOS 11.4 months, n=15 patients). The most common anti-cancer interventions among all patients were ONC201 (39 patients), temozolomide (37 patients), bevacizumab (23 patients), panobinostat (8 patients), and immune checkpoint inhibitors (3 patients each, pembrolizumab and nivolumab). In this dataset, no interventions were statistically significant in a Cox proportional hazard model, but both immune checkpoint inhibitors (HR = -1.24, p=0.11) and ONC201 (HR = -0.38, p=0.27) trended toward benefit in the entire population. The subpopulation of patients treated with ONC201 whose tumor also harbored a TP53 mutation displayed a tendency toward activity (n=8); TP53-mutant patients treated with ONC201 had a mOS of 25.0 months vs. TP53 wild-type patients treated with ONC201 had a mOS of 20.3 months. Annotation of data for additional patients is ongoing and updated analyses will be presented at the meeting.